rs879254526
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000527.5(LDLR):c.443G>A(p.Cys148Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C148R) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.443G>A | p.Cys148Tyr | missense_variant | 4/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.443G>A | p.Cys148Tyr | missense_variant | 4/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152254Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461570Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3AN XY: 727106
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152254Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74394
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen | Oct 15, 2018 | The mutation occurs at protein level at position 148 (position 127 of the mature protein) to change the amino acid cysteine to tyrosine. This change has been reported in the literature, found in patients with familial hypercholesterolemia and is associated with elevated cholesterol and LDL-C levels. It leads to a disturbed LDLR transport from the endoplasmic reticulum to the cell surface or is partially retained in the endoplasmic reticulum (ER). We observed this mutation in a patient with TC up to 380 mg/dl and LDL-C approx 310 mg/dl at the age of 10 years. PMID: 16250003, 1301956, 11462246 - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix | Dec 16, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
Pathogenic, no assertion criteria provided | research | Rajaie Cardiovascular, Medical and Research Center, Iran University of Medical Sciences | - | - - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 05, 2023 | The c.443G>A (p.C148Y) alteration is located in exon 4 (coding exon 4) of the LDLR gene. This alteration results from a G to A substitution at nucleotide position 443, causing the cysteine (C) at amino acid position 148 to be replaced by a tyrosine (Y). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant (also referred to as C127Y) has been detected in several unrelated individuals with familial hypercholesterolemia (FH) and FH cohorts (Nauck, 2001; Fouchier, 2005; Humphries, 2006; Taylor, 2007; Moradi, 2021). Other variants affecting this codon, including c.443G>C (p.C148S), have also been reported in association with FH (Slimane, 2002). This amino acid position is highly conserved in available vertebrate species. Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Villéger, 2002). Internal structural analysis indicates this variant eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 4 (Ambry internal data). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
Familial hypercholesterolemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 24, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. ClinVar contains an entry for this variant (Variation ID: 251225). This variant is also known as C127Y. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 11462246, 16389549, 17539906, 33732287). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 148 of the LDLR protein (p.Cys148Tyr). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at